ISSN 0017-8748Headache                                                                                 doi: 10.1111/j.1526...
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$MAPP Phase 3 results

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$MAPP Phase 3 results

  1. 1. ISSN 0017-8748Headache doi: 10.1111/j.1526-4610.2011.01869.x© 2011 American Headache Society Published by Wiley Periodicals, Inc.Research Submissions MAP0004, Orally Inhaled DHE: A Randomized, Controlled Study in the Acute Treatment of Migraine head_1869 507..517 Sheena K. Aurora, MD; Stephen D. Silberstein, MD; Shashidhar H. Kori, MD; Stewart J. Tepper, MD; Scott W. Borland, MS; Min Wang, PhD; David W. Dodick, MD Objective.—To evaluate the efficacy and tolerability of MAP0004 compared with placebo for a single migraine in adultmigraineurs: The FREEDOM-301 Study. Background.—Acute treatment of migraine remains a clinical challenge despite the availability of triptans and otheragents. Injectable dihydroergotamine, although effective, is considered invasive and inconvenient, and intranasal dihydroer-gotamine is associated with inconsistent systemic dosage delivery. MAP0004 is an orally inhaled formulation of dihydroergota-mine delivered to the systemic circulation. In a phase 2 study, MAP0004 provided significant early onset of pain relief (10minutes, P < .05) and sustained pain relief for up to 48 hours with a favorable adverse event profile. Methods.—A phase 3, randomized, double-blind, placebo-controlled, parallel-group, single-attack, outpatient study ofMAP0004, an inhaled dihydroergotamine was conducted at 102 sites in 903 adults with a history of episodic migraine. Patientswere randomized (1:1) to receive MAP0004 (0.63 mg emitted dose; 1.0 mg nominal dose) or placebo, administered after onsetof a migraine headache with moderate to severe pain. The co-primary endpoints were patient-assessed pain relief and absenceof photophobia, phonophobia, and nausea at 2 hours after treatment.From Swedish Headache Center, Seattle, WA, USA (S.K. Aurora); Jefferson Medical College of Thomas Jefferson University,Philadelphia, PA, USA (S.D. Silberstein); MAP Pharmaceuticals, Mountain View, CA, USA (S.H. Kori, S.W. Borland, andM. Wang); Cleveland Clinic, Neurological Center for Pain, Cleveland, OH, USA (S.J. Tepper); Mayo Clinic, Scottsdale, AZ, USA(D.W. Dodick).Address all correspondence to S.K. Aurora, Swedish Pain and Headache Center, 1101 Madison Street, Suite 200, Seattle, WA 98104,USA. To download a podcast featuring further discussion of this article, please visit www.headachejournal.orgAccepted for publication February 7, 2011.Conflict of Interest: Dr. Kori, Dr. Wang, and Mr. Borland are employees of MAP and own stock or stock options in MAP. Dr. Aurorareports having received grants/honoraria from or serving as a consultant or on the advisory board of Advanced Bionics, Alexza,Allergan, Capnia, GlaxoSmithKline, Kowa, MAP, Merck, Ortho-McNeil, Neuralieve, NuPathe, and Takeda. Dr. Silberstein reportshaving received grants or honoraria from Advanced NeuroModulation Systems, AGA, Allergan, Boston Scientific, Capnia,Coherex, Endo, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NuPathe, and Valeant. Dr. Tepper reports having received grantsand research support from ATI, GlaxoSmithKline, MAP, and Merck; serving as a consultant and on the advisory board for GSK,MAP, Merck, NuPathe, and Zogenix; and serving on the speakers bureau for GlaxoSmithKline, Valeant, and Merck. Dr. Dodickreports having received honoraria from Allergan, Merck, Neuralieve, Coherex, Kowa, Minster, NeurAxon, H. Lundbeck, Endo,Pfizer, Eli Lilly, Boston Scientific, Novartis, and MAP in addition to being a consultant to and on the advisory board of thesepharmaceutical companies. He also reports having received research funding from Advanced Neurostimulation Systems andMedtronic.Financial Statement: Role of the study sponsor: This research was funded by MAP Pharmaceuticals, Inc. MAP Pharmaceuticalsprovided financial and material support, monitoring, data collection and management, and data analysis to the authors and studyinvestigators.Clinical Trial Registration: The FREEDOM-301 study was registered at ClinicalTrials.gov (NCT00623636). 507
  2. 2. 508 April 2011 Results.—A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienceda qualifying migraine. MAP0004 was superior to placebo in all 4 co-primary endpoints: pain relief (58.7% vs 34.5%, P < .0001),phonophobia free (52.9% vs 33.8%, P < .0001), photophobia free (46.6% vs 27.2%, P < .0001), and nausea free (67.1% vs58.7%, P = .0210). Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 thanwith placebo (28.4% vs 10.1%, P < .0001). MAP0004 was well tolerated; no drug-related serious adverse events occurred. Conclusions.—In this study, MAP0004 was effective and well tolerated for the acute treatment of migraine with or withoutaura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults withmigraine compared with placebo.Key words: dihydroergotamine, migraine, oral inhalation, MAP0004, sustained pain relief, clinical trialAbbreviations: AE adverse event, DHE dihydroergotamine, e-diary electronic diary, FEV1 forced expiratory volume at 1 second, ITT intent to treat, SPF sustained pain-free, SPR sustained pain relief(Headache 2011;51:507-517) Migraine is common, with US prevalence ~6% in DHE for severe migraines, refractory migraines, andmen and ~18% in women.1,2 It is also debilitating, recurrent headaches,14 and repetitive IV DHE hasresulting in 112 million bedridden days and $13 been reported to relieve symptoms in 90% of thosebillion in annual costs to employers.3-5 Underdiagno- with refractory headache, including chronic dailysis, undertreatment, and inadequate relief with treat- headache with and without medication overuse,ment are frequently reported despite the availability short-duration headache, and cluster headache.15 IVof 7 different triptans and other options used for DHE is associated with nausea, frequently necessitat-acute treatment of migraine.1,6-9 ing pre-administration of antiemetic therapy. The Patient dissatisfaction with available therapies invasiveness and inconvenience of injectable DHEfor the acute treatment of migraine is high.6,10 In a and inconsistent systemic dosage delivery resultingquestionnaire administered in 3 headache centers to from intranasal DHE administration have limited its183 patients with migraine diagnosed according to the use for the acute treatment of migraine.14,162nd edition of the International Classification of MAP0004 (LEVADEX™, MAP Pharmaceuti-Headache Disorders (2004),11 96.4% of whom took cals, Mountain View, CA, USA) is a novel formulationtriptans alone or in combination as usual care, slow of DHE delivered by oral inhalation through theonset of action (37%), inadequate pain relief (42%), lungs to the systemic circulation using the TEMPO®recurrence/worsening of pain (50%), inability to inhaler (MAP Pharmaceuticals), designed to offerquickly function normally after taking medication consistent, convenient, and noninvasive dosing.17 The(48%), and undesirable adverse event (AE) profiles inhaled route of administration may overcome limi-(38%) were reasons cited for dissatisfaction.6 In light tations of current oral therapies in migraineurs expe-of these issues, 79% of these patients expressed a riencing gastric stasis, nausea, and vomiting, as well aswillingness to try a new medication to treat their providing more consistent drug delivery than intrana-migraine headaches.6 Undesirable AEs associated sal administration. In a phase 2 study, MAP0004 pro-with triptans, collectively known as “triptan sensa- vided a statistically significant early onset of paintions,” which may include tingling, paresthesias, chest relief (10 minutes) and meaningful sustained painpain or pressure, flushing, dizziness, and sensations of relief (SPR) for up to 48 hours with a favorable AEwarmth involving the head, neck, chest, and extremi- profile,18 including absence of nausea and relativeties, may be of concern to patients that experience lack of triptan sensation-type AEs. Pharmacokineticthem.12 studies with MAP0004 have shown that Cmax is Dihydroergotamine (DHE) has been used effec- reached in ~10 minutes, with a Cmax at least an order oftively for the acute treatment of migraine since the magnitude lower than with IV DHE but with a1940s.13 Migraine treatment guidelines recommend similar area under the curve,19 which may account for
  3. 3. Headache 509the observed decrease in concentration-dependent attacks, or seizures were also excluded. Patients with aAEs with MAP0004 compared with IV DHE.19 history of severe uncontrolled asthma, bronchospasm The primary objective of this phase 3, double- with inhaled medications, or chronic pulmonaryblind, multicenter FREEDOM-301 study was to disease other than asthma were excluded; however,evaluate the efficacy and tolerability of orally inhaled patients with controlled asthma were eligible to par-MAP0004 compared with placebo for the acute treat- ticipate in the trial and were also eligible to participatement of a single migraine with or without aura. The in the long-term open-label safety portion of the trial.0.63 mg emitted dose (1.0 mg nominal dose or 0.5 mg Standard Protocol Approvals, Registrations, andsystemic equivalent) was selected based on prior dose Patient Consents.—The FREEDOM-301 study wasfinding studies.18 The nominal dose is the dose conducted in accordance with Good Clinical Prac-metered out by the canister and delivered from the tices, International Conference on Harmonisationvalve of the device; the emitted dose is that which guidelines, applicable regulatory requirements, andcomes out of the inhaler and is received by the ethical principles of the Declaration of Helsinki ofpatient. Efficacy assessments focused on migraine 1975 (as revised in 2000).An appropriate Institutionalsymptoms at the 2-hour time point after treatment, as Review Board approved the study protocol at eachis standard in migraine studies evaluating acute phar- clinical site. Written informed consent was obtainedmacotherapies. from each potential patient prior to any protocol- related activities in accordance with Good ClinicalMETHODS Practices, the Code of Federal Regulations, and the Patients.—The study population included 903 male Health Insurance Portability and Accountability Actand female migraineurs, 18-65 years of age, with a of 1996. The first patient was enrolled in July 2008,history of episodic migraine with or without aura and the last patient completed study assessments inaccording to International Classification of Headache March 2009 at 123 centers in the USA. All studyDisorders-2 criteria.11 Eligible patients must have personnel, patients, monitors, and the sponsorbeen diagnosed with migraine for a minimum of 1 remained blinded to treatment assignment until afteryear prior to the study and, in the 6 months prior to the database was locked at completion of the double-the screening visit, suffered from an average of 2-8 blind period. The study was registered at ClinicalTri-headaches/month. Patients on migraine prophylaxis als.gov (NCT00623636).and those with a prior history of triptan treatment Procedures.—This study was a phase 3, double-were eligible for study inclusion. Eligible patients blind, multicenter comparison of MAP0004 0.6 mgwere required to complete a spirometry evaluation, emitted dose (1.0 mg nominal dose or 0.5 mg systemicwith forced expiratory volume at 1 second equivalent) and placebo in the acute treatment of a(FEV1) Ն50% predicted and FEV1/forced vital single migraine. The double-blind portion of the studycapacity ratio Ն70% predicted. Eligible patients must reported here consisted of 3 clinic visits. During visitalso have had a normal or clinically insignificant 1, patients underwent baseline evaluations, wereelectrocardiogram. trained on use of the inhaler and electronic diary Patients with a known allergy or hypersensitivity (e-diary), and completed the Headache Impact Testto DHE or who were users of any concomitant questionnaire.20 At visit 2, patients were required toexcluded medication were ineligible. Participation in have reported at least 2 but not more than 8 migrainesanother MAP0004 trial, any other clinical trial in the and to have had Ն20 headache-free days on theirpast 30 days, or a history of hemiplegic or basilar e-diary during the previous 28-day run-in period.migraine were causes for exlusion. Patients with Ն2 Patients had to continue to satisfy all eligibility crite-coronary artery disease risk factors, history of coro- ria to be randomized.nary artery disease, coronary vasospasm, aortic aneu- Eligible patients were randomly assigned in a 1:1rysm, peripheral vascular disease or other ischemic ratio without stratification to receive either MAP0004diseases, or a history of stroke, transient ischemic or placebo. Randomization was centralized and
  4. 4. 510 April 2011performed by an automated interactive voice recog- the 2-hour period; proportion of patients with painnition system. Randomized patients were instructed relief at 4 hours; and proportion of patients with painto use study drug to treat a single qualifying migraine, relief at 10 minutes. SPR from 2-24 hours was defineddefined by the Headache Classification Committee of as the proportion of patients reporting pain relief at 2the International Headache Society (2nd edition)11 as hours which was subsequently maintained from 2-24a migraine with moderate or severe pain (patient hours with no rescue medication use. Time to painassessed) that was either unilateral, throbbing (pul- relief was defined as the time when pain relief (mild orsating), or worsened with activity and occurred in the no pain) was first observed and maintained through 2presence of either nausea, vomiting, or both phono- hours with no rescue medication use at or prior to thisphobia and photophobia. No triptan or ergot admin- time point. Pain relief at 4 hours and at 10 minutes wasistration was allowed within the 24 hours prior to defined similarly to the 2-hour pain relief endpoint.migraine onset. The e-diary directed patients to treat Other prespecified endpoints for analysisif the migraine was qualifying. The active inhaler con- included time to pain freedom in the 2-hour periodtained DHE mesylate suspended in a mixture of posttreatment; proportion of patients pain-free at 2hydrofluoroalkane propellants, while the placebo hours; proportion of patients with SPR from 2-48inhaler contained only the hydrofluoroalkane hours posttreatment; and proportion of patients whomixture. Patients returned for visit 3 for follow-up were sustained pain-free (SPF) from 2-24 hours andevaluations after treatment, and eligible patients 2-48 hours posttreatment, with no rescue medicationwere given the option to continue in a long-term use at or prior to the identified time point. Time toopen-label safety period if required baseline evalua- pain freedom, pain freedom at 2 hours, and SPF weretions were completed. defined similarly to the time to pain relief, pain relief, During the double-blind phase, patients recorded and SPR endpoints, respectively, but with a require-time of onset of their qualifying migraine, severity of ment of no pain.migraine symptoms, rescue medication use, and pres- Statistical Analysis.—Sample size was determinedence or absence of allodynia and other migraine using a 2-group continuity corrected chi-square testattributes at baseline, upon administration of study with a 2-sided, 5% type I error rate based on thedrug, and at several time points up to 48 hours after following assumptions: rates of pain relief of 60% vstreatment in the e-diary. Pain, nausea, photophobia, 40%, freedom from nausea of 71.5% vs 60%, freedomand phonophobia were assessed using a 4-point scale from photophobia of 55% vs 40%, and freedom fromfor severity (0-no symptoms, 1-mild symptoms, phonophobia of 55% vs 40% for MAP0004 vs2-moderate symptoms, 3-severe symptoms). All AEs placebo. Assuming a 10% dropout rate at treatmentreported by patients during treatment were recorded, period end, approximately 850 patients were to beand incidences of serious, severe, and treatment- randomized to obtain 766 treated patients to providerelated AEs were tabulated. an overall 86% power for a 2-sided test with 5% type Outcome Measures.—This study tested the hypoth- I error rate.esis that MAP0004 would be superior to placebo for The intent to treat (ITT) population was definedall 4 co-primary endpoints at the 2-hour time point. as all randomized patients and was primarily used toThese endpoints, derived from US Food and Drug describe patient disposition. The predeterminedAdministration requirements for regulatory modified ITT population, defined as all randomizedapproval, included the proportion of patients who patients who reported a qualifying migraine, receivedachieved pain relief and those who were at least 1 dose of study drug, and reported a posttreat-photophobia-free, phonophobia-free, and nausea-free ment efficacy evaluation for Ն1 time point at orat 2 hours posttreatment with no rescue medication before the 2-hour time point, was used for theuse prior to the 2-hour time point. Four secondary primary analysis of efficacy. The safety populationendpoints were also analyzed: proportion of patients consisted of all patients who received 1 dose of studywith SPR from 2-24 hours; time to pain relief during drug and had Ն1 posttreatment safety evaluation.
  5. 5. Headache 511 Each co-primary and secondary endpoint was in Figure 1. Baseline demographic, disability, and pul-tested for treatment effect by comparing MAP0004 monary function measures and migraine characteris-and placebo-treated patients. A gate-keeping strategy tics at time of treatment were comparable betweenwas employed to control for the family-wise error the MAP0004 and placebo groups with no baselinerate of 0.05. If all 4 co-primary endpoints reached discrepancies identified (Table 1). The mean Head-statistical significance, the first identified secondary ache Impact Test score at baseline was 66, placingendpoint (proportion of patients with SPR 2-24 patients in the severely impacted range.At the time ofhours) was tested for significance. Sequential signifi- treatment, 55% of patients in the MAP0004 groupcance testing of other secondary endpoints proceeded reported moderate headache pain, 45% reportedonly if the preceding endpoint reached significance, severe headache pain, and 55% of patients hadotherwise no further testing was performed. Time to allodynia.pain relief and freedom were analyzed using a log- Efficacy.—The proportion of patients achievingrank test and Kaplan-Meier survival analysis tech- each of the 4 co-primary endpoints was statisticallyniques. All other prespecified and post hoc endpoints significantly greater for MAP0004 compared withwere analyzed using the Cochran-Mantel-Haenszel placebo at 2 hours posttreatment (Table 2). Paintest, controlling for each respective baseline score, but relief at 2 hours was observed in 59% of patients innot adjusted for multiplicity. All endpoints were ana- the MAP0004 group compared with 35% in thelyzed at a 2-sided, 5% significance level. placebo group (P < .0001, Absolute Risk Reduction [ARR] = 24%, 95% confidence interval [CI]RESULTS 17-31%, number-needed-to-treat [NNT] = 4.13). The A total of 903 patients (450 active, 453 placebo) phonophobia-free rate for MAP0004 compared withwere randomized into the study at 102 US centers, placebo was 53% vs 34% (P < .0001, ARR = 19%,and 811 experienced a qualifying migraine and self- 95% CI 12-26%, NNT = 5.22), the photophobia-freetreated with study medication. The modified ITT rate was 47% vs 27% (P < .0001, ARR = 19%, 95%population included 395 patients in the MAP0004 CI 13-26%, NNT = 5.16), and the nausea-free ratetreatment group and 397 patients in the placebo was 67% vs 59% (P = .0210, ARR = 8%, 95% CIgroup with randomized patient dispositions as shown 2-15%, NNT = 12.15). Randomized n=903 MAP0004 Placebo ITT population ITT population n=450 n=453 No qualifying migraine 43 No qualifying migraine 49 Did not receive dose 9 Did not receive dose 6 No follow-up assessment 3 No follow-up assessment 1 mITT Population mITT Population n=395 n=397 Safety Safety Population Population n=404 n=401Fig 1.—Disposition of randomized patients.
  6. 6. 512 April 2011 Table 1.—Baseline Patient Demographics and Characteristics of the Treated Migraine in the Double-Blind Phase (mITT Population) MAP0004 (n = 395) Placebo (n = 397)Baseline Age, mean (SD), year 40.5 (11.3) 39.6 (11.7) Female, No. (%) 363 (91.9) 362 (91.2) Body mass index, mean (SD), kg/m2 28.0 (6.6) 27.9 (6.4) Race, No. (%) White 348 (88.1) 335 (84.4) Black 35 (8.9) 47 (11.8) Asian 5 (1.3) 12 (3.0) Other 7 (1.7) 3 (0.8)HIT-6 score, mean (SD) 65.5 (4.9) 65.6 (5.0)Percent predicted FEV1, mean (SD) 91.8 (11.9) 92.9 (12.5)Characteristics of migraine headache at time of treatment, No. (%) Moderate pain 217 (54.9) 209 (52.6) Severe pain 178 (45.1) 188 (47.4) Nausea present 271 (68.6) 280 (70.5) Photophobia present 380 (96.2) 382 (96.2) Phonophobia present 364 (92.2) 366 (92.2) Allodynia present 216 (54.7) 202 (50.9)FEV1 = forced expiratory volume at 1 second; HIT-6 = Headache Impact Test; mITT = modified intent to treat; SD = standarddeviation. Table 2.—Proportion of Patients Achieving Co-Primary and Secondary Endpoints (mITT Population) MAP0004n/N (%) (Orally Inhaled DHE) Placebo P valuePain relief At 10 minutes (all) 33/388 (9) 22/387 (6) .1584 Moderate pain 24/213 (11) 20/200 (10) .6768 Severe pain 9/166 (5) 2/187 (1) .0242 At 2 hours (all) 232/395 (59) 137/397 (35) <.0001 Moderate pain 152/217 (70) 87/209 (42) <.0001 Severe pain 80/178 (45) 50/188 (27) .0003 At 4 hours 254/393 (65) 144/391 (37) <.0001Time to pain relief* <.05 @ 30 minutesSustained pain relief 2-24 h 167/382 (44) 76/387 (20) <.0001Phonophobia free at 2 h 209/395 (53) 134/397 (34) <.0001Photophobia free at 2 h 184/395 (47) 108/397 (27) <.0001Nausea free at 2 h 265/395 (67) 233/397 (59) .0210*Time to pain relief is the first time at which there was a statistically significant separation of active treatment from placebo thatwas also then sustained out to 2 hours.Bold type indicates a co-primary endpoint.DHE = dihydroergotamine; mITT = modified intent to treat.
  7. 7. Headache 513 The response rates for all 4 secondary endpoints (4%), cough (2%), and vomiting (2%) occurred morewere either statistically or numerically superior for often with MAP0004 than with placebo. In particular,MAP0004 compared with placebo (Table 2). The SPR incidence of nausea reported as an AE for MAP00042-24 hour rate was significantly greater (P < .0001) for was 4% compared with 2% for placebo. Triptan sen-the MAP0004 group vs the placebo group (Table 2). sations in the MAP0004 group such as chest discom-Time to onset of pain relief was calculated to be 30 fort (1%), chest pain (0%), and paresthesias (0.5%)minutes (P = .0266). The proportion of patients expe- were rare and comparable to placebo. Mean changeriencing pain relief at 4 hours was significantly greater in pulmonary function as measured by FEV1 from(P < .0001) for the MAP0004 group vs the placebo baseline to end of the double-blind period wasgroup. Finally, the proportion of patients experiencing +0.02 L (0.7% increase) for both treatment groups. Apain relief at 10 minutes, while not statistically signifi- Ն20% decrease in FEV1 from baseline to end of thecant, was 50% greater in MAP0004 patients vs double-blind treatment period, considered clinicallyplacebo patients. relevant, was observed in 4 (1.0%) patients in the The response rates for several other prespecified MAP0004 group and 3 (0.7%) in the placebo group.endpoints favored MAP0004 compared with placebo Other evaluations showed no clinically relevant dif-(as defined by P < .05), without multiplicity adjust- ferences between treatment groups.ments (Table 3). Two-hour pain relief was significantwith MAP0004 regardless of when treatment DISCUSSIONoccurred; within <1 hour and between 1-4 hours after MAP0004 was effective in relieving all symptomsonset (P < .0001); >4-<8 hours and >8 hours after of migraine with a favorable AE profile in the presentonset (P < .05) compared with placebo. Time to pain study. The 2-hour response rates were similar to orfreedom was 23 minutes (P = .0203). Pain freedom at higher than those reported in recently published2 hours was 28% for MAP0004 and 10% for placebo phase 3 trials of other migraine investigations, even(P < .0001). Pain relief at both 24 and 48 hours was though there were more migraineurs treated instatistically significant for the MAP0004 group vs the this study that had severe pain at the time ofplacebo group (57% vs 35% and 49% vs 32%, respec- treatment.21-23 In total, 46.2% of migraineurs in thistively; P < .0001 for each) (Fig. 2a). Significantly more study reported severe migraine pain, in contrast topatients in the MAP0004 group achieved pain 36.6% and 40.6% in the reported sumatriptan-freedom at 24 and 48 hours (48% vs 28% and 45% vs naproxen studies21 and 37.5% and 35.5% in reported28%, respectively; P < .0001 for each) (Fig. 2b) vs telcagepant trials.22,23patients receiving placebo. The SPR rate from 2-48 The speed of onset of any given drug is depen-hours was significantly greater for the MAP0004 dent, at least in part, on its rate of absorption.24 In agroup than for the placebo group, as were the SPF prior study, MAP0004 provided statistically signifi-2-24 hours and 2-48 hours measures (all P < .0001), as cant pain relief at 10 minutes, which is likely related toshown in Table 2. Significantly more patients used its rapid absorption through the lung. In the presentrescue medication by 22 hours after treatment in the study, although more patients taking MAP0004placebo group compared with the MAP0004 group achieved pain relief at 10 minutes compared with(60% vs 43%, P < .0001). those taking placebo, a statistically significant differ- Safety and Tolerability.—No drug-related serious ence between the 2 treatments was not evident untilAEs were reported during the study. At least 1 AE 30 minutes. This finding is similar to that found inwas reported in each of 126 patients (31.2%) in the clinical studies of several of the marketed triptans.19MAP0004 group compared with 101 patients (25.2%) Interestingly, patients who had severe pain at time ofin the placebo group and 140 patients (17.4%; both treatment achieved statistically significant pain relieftreatment groups combined) during the run-in period compared with placebo at 10 minutes. Further studies(Table 4). Of the AEs that occurred in any treatment to systematically evaluate the onset of action ofgroup at a rate Ն2%, only product taste (6%), nausea MAP0004 may be warranted, as this pivotal phase 3
  8. 8. 514 April 2011 Table 3.—Proportion of Patients Achieving Additional Prespecified Endpoints (mITT Population) MAP0004 (Orally Inhaled DHE) Placebo P valuePain relief, n/N (%) At 30 minutes 111/385 (29) 83/385 (22) .0245 At 60 minutes 187/391 (48) 110/391 (28) <.0001 At 2 hours Treated within 1 hour of onset 74/112 (66) 48/118 (41) <.0001* Treated >1-4 hours after onset 91/152 (60) 59/169 (35) <.0001* Treated >4-< 8 hours after onset 36/68 (53) 16/53 (30) <.05* Treated >8 hours after onset 26/53 (49) 11/46 (24) <.05* At 4 hours 254/393 (65) 144/391 (37) <.0001 At 24 hours 218/381 (57) 135/387 (35) <.0001 At 48 hours 174/356 (49) 118/371 (32) <.0001Pain free, n/N (%) At 10 minutes 4/369 (1) 2/370 (1) .4350 At 30 minutes 20/385 (5) 5/385 (1) .0024 At 60 minutes 59/391 (15) 18/391 (5) <.0001 At 2 hours 112/395 (28) 40/397 (10) <.0001 At 4 hours 155/394 (39) 65/391 (17) <.0001 At 24 hours 187/386 (48) 108/390 (28) <.0001 At 48 hours 164/367 (45) 107/377 (28) <.0001Time to pain free‡ <.05 @ 23 minutesSustained pain relief 2-48 hours 129/362 (36) 62/376 (17) <.0001Sustained pain-free 2-24 hours 90/390 (23) 26/390 (7) <.0001 2-48 hours 67/379 (18) 23/389 (6) <.0001Recurrence Within 24 hours 15/232 (6) 21/137 (15) .01*Phonophobia free At 10 minutes 54/370 (15) 47/369 (13) .5726 At 30 minutes 105/386 (27) 79/384 (21) .0286 At 60 minutes 153/391 (39) 100/391 (26) <.0001 At 4 hours 223/392 (57) 130/390 (33) <.0001Photophobia free At 10 minutes 32/370 (9) 26/370 (7) .4460 At 30 minutes 69/386 (18) 53/385 (14) .1237 At 60 minutes 121/391 (31) 85/391 (22) .0032 At 4 hours 206/392 (53) 119/391 (30) <.0001Nausea free At 10 minutes 133/370 (36) 126/370 (34) .9409 At 30 minutes 159/386 (41) 182/383 (48) .0169 At 60 minutes 208/391 (53) 214/390 (55) .4028 At 4 hours 251/390 (64) 179/387 (46) <.0001* Statistical comparison was not part of the original planned analyses. Analysis performed post hoc without adjustments for multiplecomparisons.‡Time to pain freedom is the first time at which there was a statistically significant separation of active treatment from placebo thatwas also then sustained out to 2 hours.DHE = dihydroergotamine; mITT = modified intent to treat.study was not specifically designed to evaluate time of cantly lower recurrence rates were observed afteronset. subcutaneous (SC) DHE treatment in a head-to-head Dihydroergotamine is generally considered to comparison vs SC sumatriptan.25 Potential explana-provide prolonged pain relief, and statistically signifi- tions include longer drug half-life, prolonged binding
  9. 9. Headache 515 a 100 MAP0004 Placebo 80 † † % Patients † 60 † † 40 * 20 0 33/388 22/387 111/385 83/385 187/391 110/391 232/395 137/397 254/393 144/391 218/381 135/387 174/356 118/371 10 min 30 min 60 min 2 hr 4 hr 24 hr 48 hr Posttreatment Pain Relief 0-48 Hr b 100 MAP0004 Placebo 80 % Patients 60 † † † 40 † 20 † * 0 4/369 2/370 20/385 5/385 59/391 18/391 112/395 40/397 155/394 65/391 187/386 108/390 164/367 107/377 10 min 30 min 60 min 2 hr 4 hr 24 hr 48 hr Posttreatment Pain Freedom 0-48 HrFig 2.—Posttreatment pain relief (a) and pain freedom (b) from 0-48 hours. *P < .05; †P < .0001.to target receptors, and earlier and more complete cant for MAP0004. Headache recurrence over 24intervention in the migraine event cascade. The hours, defined as the return of headache to moderatepresent data confirm the prolonged effect of DHE. or severe within 24 hours of dosing in subjects whoBoth SPR and SPF from 2-24 hours and 2-48 hours had pain relief within 2 hours of dosing, was 6% forwere significant for MAP0004 compared with placebo MAP0004 and 15% for placebo.(all P < .0001), illustrating this effect. The SPF 2- to MAP0004 was well tolerated in this study. As24-hour therapeutic gain observed with MAP0004 anticipated, the rate of nausea was low. The low ratewas 16% and is similar to 2- to 24-hour SPF values of AEs observed here is similar to that seen in previ-observed in phase 3 trials of sumatriptan/naproxen ous studies18,19,26 with MAP0004 and may beand telcagepant.21,22 SPR 2-48 and SPF 2-48 hour rates explained by the pharmacokinetic profile and theare rarely reported but were both statistically signifi- lower Cmax of orally inhaled DHE compared with IV
  10. 10. 516 April 2011 Table 4.—Incidence of Adverse Events Occurring in Ն2% of Patients During the Run-In Period and During Double-Blind Treatment With MAP0004 and Placebo No. (%) of PatientsAdverse Event Run-In Period (n = 805) MAP0004 (n = 404) Placebo (n = 401)Any event 140 (17.4) 126 (31.2) 101 (25.2)Cough 4 (0.5) 10 (2.5) 5 (1.2)Nasopharyngitis 14 (1.7) 8 (2.0) 14 (3.5)Nausea 1 (0.1) 18 (4.5) 8 (2.0)Product taste 0 26 (6.4) 7 (1.7)Upper respiratory tract infection 22 (2.7) 12 (3.0) 12 (3.0)Vomiting 1 (0.1) 8 (2.0) 3 (0.7)DHE.18 Triptan sensations including chest pain, chest Category 2discomfort, paresthesias, and flushing were rare. Lack (a) Drafting the Manuscriptof statistically significant changes in pulmonary func- Shashidhar H. Kori; Scott W. Borland; Sheena K.tion and laboratory measures support the safety of Aurorathe inhaled route as an alternative to address limita- (b) Revising It for Intellectual Contenttions of oral, nasal, and injectable/IV therapies. Stephen D. Silberstein; David W. Dodick; Stewart An open-label extension portion of this study J. Tepperexamining long-term safety is ongoing, and additional Category 3studies are planned to further evaluate the efficacy, (a) Final Approval of the Completed Manuscripttolerability, and safety profile of MAP0004. Sheena K. Aurora; Shashidhar H. Kori; Stephen Acknowledgments: The authors thank John D. Silberstein; David W. Dodick; Stewart J.Simmons, MD, for editorial assistance with manuscript Tepper; Scott W. Borland; Min Wangpreparation. Dr. Kori and Mr. Borland prepared the firstdraft of the manuscript with critical revisions by all of theauthors for important intellectual content. Dr. Aurora had REFERENCESfull access to all the data in the study and takes responsi- 1. Lipton RB, Stewart WF, Diamond S, Diamond ML,bility for the integrity of the data and the accuracy of the Reed M. Prevalence and burden of migraine in thedata analysis. United States: Data from the American Migraine Study II. Headache. 2001;41:646-657. 2. Stewart WF, Lipton RB, Celentano DD, Reed ML.STATEMENT OF AUTHORSHIP Prevalence of migraine headache in the UnitedCategory 1 States. Relation to age, income, race, and other(a) Conception and Design sociodemographic factors. JAMA. 1992;267:64-69. 3. Becker C, Brobert GP, Almqvist PM, Johansson S, Sheena K. Aurora; Shashidhar H. Kori; Stephen Jick SS, Meier CR. Migraine incidence, comorbidity D. Silberstein and health resource utilization in the UK. Cephalal-(b) Acquisition of Data gia. 2008;28:57-64. Sheena K. Aurora; Shashidhar H. Kori; Stephen 4. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed D. Silberstein; Scott W. Borland; Stewart J. Tepper ML, Stewart WF. Migraine prevalence, disease(c) Analysis and Interpretation of Data burden, and the need for preventive therapy. Neu- Sheena K. Aurora; Shashidhar H. Kori; Stephen rology. 2007;68:343-349. D. Silberstein; David W. Dodick; Min Wang; 5. Stovner L, Hagen K, Jensen R, et al. The global Stewart J. Tepper, Scott W. Borland burden of headache: A documentation of headache
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